Vav3-induced cytoskeletal dynamics contribute to heterotypic properties of endothelial barriers
Vav3-induced cytoskeletal dynamics contribute to heterotypic properties of endothelial barriers
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DOI：
10.1083/jcb.201706041
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发表时间：
2018-08-01
影响因子：
7.8
通讯作者：
Iruela-Arispe, M. Luisa
中科院分区：
文献类型：
--
作者：
Hilfenhaus, Georg;Dai Phuong Nguyen;Iruela-Arispe, M. Luisa
通过多种细胞-细胞和细胞-基质相互作用，上皮和内皮层形成紧密的屏障。细胞骨架的调节剂有助于屏障的稳定性，并作为血管通透性的变阻器。在这项研究中，我们试图确定构成血管屏障多样性基础的细胞骨架调节因子。为了实现这一目标，我们将功能和结构屏障特征与来自不同血管床的内皮细胞（ECs）的基因表达联系起来。在确定的候选细胞中，我们发现鸟苷核苷酸交换因子Vav3仅在微血管内皮细胞中表达，并与高抗性屏障表型密切相关。Vav3在大动脉和脑ECs中的异位表达显著增强了肌动蛋白细胞骨架的屏障抵抗和皮层重排。在机制上，我们发现Vav3的屏障作用依赖于它的Dbl同源结构域和Rap1的下游激活。重要的是，Vav3在体内失活导致血管渗漏增加，突出了其作为屏障稳定性关键调节剂的功能。
Through multiple cell-cell and cell-matrix interactions, epithelial and endothelial sheets form tight barriers. Modulators of the cytoskeleton contribute to barrier stability and act as rheostats of vascular permeability. In this study, we sought to identify cytoskeletal regulators that underlie barrier diversity across vessels. To achieve this, we correlated functional and structural barrier features to gene expression of endothelial cells (ECs) derived from different vascular beds. Within a subset of identified candidates, we found that the guanosine nucleotide exchange factor Vav3 was exclusively expressed by microvascular ECs and was closely associated with a high-resistance barrier phenotype. Ectopic expression of Vav3 in large artery and brain ECs significantly enhanced barrier resistance and cortical rearrangement of the actin cytoskeleton. Mechanistically, we found that the barrier effect of Vav3 is dependent on its Dbl homology domain and downstream activation of Rap1. Importantly, inactivation of Vav3 in vivo resulted in increased vascular leakage, highlighting its function as a key regulator of barrier stability.